Search

Purpose: To investigate the incidence of and variables associated with clinically evident fat necrosis in women treated on a protocol of high-dose-rate (HDR) brachytherapy alone without external-beam whole-breast irradiation for early-stage breast carcinoma. Methods and Materials: From 6/1997 until 8/1999, 30 women diagnosed with Stage I or II breast carcinoma underwent surgical excision and postoperative irradiation via HDR brachytherapy implant as part of a multi-institutional clinical Phase I/II protocol. Patients eligible included those with T1, T2, N0, N1 (≤ 3 nodes positive), M0 tumors of nonlobular histology with negative surgical margins, no extracapsular lymph-node extension, and a negative postexcision mammogram. Brachytherapy catheters were placed at the initial excision, re-excision, or at the time of axillary sampling. Direct visualization, surgical clips, ultrasound, or CT scans assisted in delineating the target volume defined as the excision cavity plus 2-cm margin. High activity 192 Ir (3–10 Ci) was used to deliver 340 cGy per fraction, 2 fractions per day, for 5 consecutive days to a total dose of 34 Gy to the target volume. Source position and dwell times were calculated using standard volume optimization techniques. Dosimetric analyses were performed with three-dimensional postimplant dose and volume reconstructions. The median follow-up of all patients was 24 months (range, 12–36 months). Results: Eight patients (crude incidence of 27%) developed clinically evident fat necrosis postimplant in the treated breast. Fat necrosis was determined by clinical presentation including pain and swelling in the treated volume, computed tomography, and/or biopsy. All symptomatic patients (7 of 8 cases) were successfully treated with 3 to 12 months of conservative management. Continuous variables that were found to be associated significantly with fat necrosis included the number of source dwell positions ( p = 0.04), and the volume of tissue which received fractional doses of 340 cGy, 510 cGy, and 680 cGy ( p = 0.03, p=0.01, and p = 0.01, respectively). Other continuous variables including patient age, total excised tissue volume, tumor size, number of catheters, number of days the catheters were in place, planar separation, dose homogeneity index (DHI), and uniformity index (UI) were not significant. Discrete variables including the presence/absence of DCIS, sentinel versus full axillary nodal assessment, receptor status, presence/absence of diabetes, and the use of chemotherapy or hormone therapy were not found to have a significant association with the risk of fat necrosis. Conclusions: In this study of HDR brachytherapy of the breast tumor excision cavity plus margin, treatment was planned and delivered in accordance with the dosimetric parameters of the protocol resulting in a high degree of target volume dose homogeneity. Nonetheless, at a median follow-up of 24 months, a high rate of clinically definable fat necrosis occurred. The overall implant volume as reflected in the number of source dwell positions and the volume of breast tissue receiving fractional doses of 340, 510, and 680 cGy were significantly associated with fat necrosis. Future dosimetric optimization algorithms for HDR breast brachytherapy will need to include these factors to minimize the risk of fat necrosis.

Purpose: To investigate the feasibility, toxicity, cosmetic outcome, and local control of high-dose-rate (HDR) brachytherapy alone without whole breast external beam irradiation for early-stage breast carcinoma. Methods and Materials: Between June 1997 and August 1999, 32 women diagnosed with a total of 33 AJCC Stage I/II breast carcinomas underwent surgical breast excision and postoperative irradiation using HDR brachytherapy interstitial implantation as part of a multi-institutional clinical Phase I/II protocol. Eligible patients included those with T1, T2, N0, N1 (≤3 nodes positive), and M0 tumors of nonlobular histologic features with negative surgical margins, no extracapsular lymph node extension, and a negative postexcision mammogram. Brachytherapy catheters were placed at the initial excision, reexcision, or either sentinel or full-axillary sampling. Direct visualization, surgical clips, and ultrasound and/or CT scan assisted in the delineation of the target volume, defined as the excision cavity plus a 2-cm margin. High-activity 192 Ir (3–10 Ci) was used to deliver 340 cGy/fraction, 2 fractions/d, for 5 consecutive days, to a total dose of 34 Gy to the target volume. Source position and dwell times were calculated using standard volume optimization techniques. Results: The median follow-up of all patients was 33 months, and the mean patient age was 63 years. The mean tumor size was 1.3 cm, and 55% had an extensive intraductal component. Three patients had positive axillary nodes. Two patients experienced moderate perioperative pain that required narcotic analgesics. No peri- or postoperative infections occurred. No wound healing problems and no significant skin reactions related to the implant developed. The Radiation Therapy Oncology Group late radiation morbidity scoring scheme was applied to the entire 33-case cohort. In the assessment of the skin, 30 cases were Grade 0–1 and 3 cases were Grade 2. Subcutaneous toxicity was scored as 11 patients with Grade 0, 3 with Grade 1, 8 with Grade 2, 3 with Grade 3, and 8 with Grade 4. Clinically evident fat necrosis occurred in 8 patients at a median of 7.5 months after HDR brachytherapy completion. The only variables significantly associated with Grade 3–4 toxicity were the number of source dwell positions and the volume of tissue encompassed by the prescription isodose shell. The global cosmetic scores after a minimum of 18 months' follow-up were 0 cases with poor, 4 with fair, 5 with good, and 24 with excellent scores. One case of ipsilateral breast tumor recurrence was diagnosed 23 months after HDR brachytherapy, for a 4-year actuarial recurrence rate of 3%. This failure appeared to be a new primary tumor, because it was histologically distinct from the initial tumor and was located 9 cm from the initial tumor bed and 3 cm from the edge of the implant volume. Conclusion: Radiotherapy of the tumor bed alone with HDR interstitial brachytherapy is associated with a 33% incidence of Grade 3–4 s.c. toxicity, but with generally favorable overall cosmetic results. The risk of toxicity appears to be primarily related to the implant volume. With limited follow-up, the incidence of ipsilateral breast tumor recurrence was low.

Purpose: To assess the effect of local-regional radiotherapy (RT) on the outcome of breast cancer patients with ≥ 10 positive axillary lymph nodes who have received modern conventional or high-dose systemic therapy. Methods and Materials: A total of 55 women with local-regionally confined breast cancer involving 10 or more axillary nodes were treated between October 1983 and January 1996. Local-regional therapy consisted of modified radical mastectomy in 39 and breast-conserving surgery in 16. Postoperative radiotherapy was given to 44 of the 55 patients. Radiotherapy consisted of tangential fields to the chest wall or intact breast to a median dose of 50.40 Gy. A total of 86% (38 of 44) received regional nodal irradiation as follows: 35 patients received RT to the supraclavicular (SC) region and axillary midplane to a median dose of 50.40 Gy and 46.20 Gy, respectively; 3 patients received RT to the SC region without inclusion of the axilla to a median dose of 50.40 Gy. All patients received adjuvant standard-dose systemic chemotherapy, 9 of whom received additional intensification chemotherapy followed by autologous bone-marrow transplant (ABMT) or peripheral blood stem-cell transplant (PBSC). Twenty-five patients received adjuvant tamoxifen. Results: With a median follow-up of 30 months, the crude overall survival (OS) and disease-free survival (DFS) for the entire group were 67% and 53%, respectively. On univariate analysis of various clinical, pathological, and therapy-related features, radiotherapy emerged as the most important factor influencing the relapse rate. The addition of RT was significantly associated with an improved DFS ( p = 0.003), specifically by prolonging the time to disease progression. The median time to failure was 61 months and 12.5 months with and without RT, respectively. Patients receiving RT also appeared to survive longer; however, the groups were not statistically different ( p = 0.10). Analysis of the patterns of failure showed local-regional recurrence (LRR) as the first site of failure in 12 (22%) of 55 and distant failure in 20 (36%) of 55. Univariate results revealed both radiotherapy and tamoxifen to be significantly associated with decreased LRR rates ( p = 0.0001 and p = 0.03, respectively); only RT remained independently significant on multivariate analysis. Conclusion: Local-regional radiotherapy is an essential component of the management of breast cancer patients with extensive nodal involvement, despite the use of contemporary adjuvant chemotherapy including high-dose regimens with autologous rescue. In addition to the expected improvement in LRR, radiotherapy is also associated with significantly prolonged DFS and a trend for improvement in OS.

Purpose: Young age and extensive intraductal component (EIC) histology have been shown to be associated with increased local recurrence in women treated with breast conservation therapy. This study was conducted to determine if the status of the lumpectomy specimen margin consistently predicted for residual tumor burden risk irrespective of these variables. Methods and Materials: As part of an institutional prospective approach for breast conservation therapy (BCT), 265 cases with AJCC Stage I/II carcinoma with an initial excision margin that was ≤2 mm or indeterminate were subjected to reexcision. The probability of residual tumor (+RE) was evaluated with respect to tumor size, histopathologic subtype (invasive ductal carcinoma, invasive ductal carcinoma with an EIC, and invasive lobular carcinoma), relative closeness of the measured margin, and the extent of margin positivity graded as focal, minimal, moderate, or extensive. The amount of residual tumor was graded as microscopic, small, medium, or large. All variables were analyzed for patient age ≤45 or >45 years. Results: There was no significant difference in the incidence of a +RE according to age ≤45 versus >45 years when the margin was >0 ≤2 mm. Of the patients aged ≤45 years, the incidence of a +RE with a margin that was positive as compared to >0 ≤2 mm was 71% vs. 23%, respectively ( p = 0.002). For women >45 years old, the difference in the incidence of +RE comparing margins that were positive or >0 ≤2 mm was not significant at 50% vs. 40%, respectively ( p = 0.23). For all cases in aggregate, age ≤45 years was associated with a greater incidence of +RE as compared to patients aged >45 years with the discrepant incidence of a +RE by age strata most pronounced for focally positive margins (60% vs. 18%; p ≤ 0.05). In a logistic regression analysis, age (per year, as a continuous variable) and an EIC histology were significantly associated with the probability of a +RE (odds ratio [OR] = 0.80, p = 0.05 and OR=1.9, p = 0.01, respectively). Tumor size was not significant ( p = 0.23). In patients with an EIC histology, margin status is generally less predictive for differences in the incidence of a +RE. Further, the overall magnitude of difference in the incidence of a +RE related to age appears to be minimized when an EIC histology is present. In contrast, for cases classified as having non-EIC histology, there is a near-linear relationship for both age strata with respect to margin status and the incidence of a +RE. When histology is classified as non-EIC, age ≤45 years is consistently associated with a greater risk of residual tumor for all margin status categories. When the extent of margin positivity was graded as focal or minimal, residual tumor was semiquantitatively estimated as a medium/large amount in 33% versus 26% of cases aged ≤45 or >45 years, respectively ( p = 0.62). Conclusion: For positive lumpectomy specimen margins, younger age is associated with an increased residual tumor risk. An EIC histology appears to be associated with an elevated risk of residual tumor irrespective of age and may undermine the predictive utility of margin status. Therefore, age and an EIC histology should be factored into risk assessments for residual tumor that rely upon margin assessment.

Purpose: A prospectively applied treatment policy for breast-conserving therapy used margin assessment as the exclusive guide to the intensity of therapy directed at the tumor-bearing quadrant. Methods and Materials: From 1982–1994, there were 509 treated Stage I and II breast carcinomas with a median follow-up of 72 months. For operational purposes, tumor excision margins were prospectively defined as: > 5 mm, 2.1–5 mm, > 0 ≤ 2 mm, and positive. If a margin was assessed as ≤2 mm or indeterminate, and it was deemed cosmetically feasible, a reexcision of the tumor bed would be performed. All patients received whole breast irradiation to 50–50.4 Gy. The following scheme for tumor bed boost irradiation as a function of final margin status (FMS) was observed: (a) Minimal risk = no tumor found on reexcision, no boost performed; (b) low risk = FMS > 5 mm, boost of 10 Gy; intermediate risk = FMS 2.1–5 mm, boost to 14 Gy; high risk = FMS ≤ 2 mm or positive, boost to 20 Gy. Cases were analyzed for local failure (LF) with respect to histology (invasive ductal (IDC), IDC with associated DCIS (IDC/DCIS), invasive lobular (ILC)), age, tumor size, total excision volume, reexcision, total dose, tamoxifen therapy, and chemotherapy. Results: There were 19 breast recurrences for a Kaplan–Meier local failure rate for all cases at 5 and 10 years of 2.7% and 7.1%, respectively. Local failure in the first 4 years of follow-up was rare, with a mean annual incidence rate of 0.25% that rose to a mean of 1.1% in subsequent years. Univariate results of Cox proportional hazards regression survival models found positive FMS (p = 0.02), IDC/DCIS (p = 0.04) and age (0.0006) as significantly associated with local failure. In a multivariable model of FMS and IDC/DCIS, FMS retained significance (p = 0.01) but IDC/DCIS was borderline (p = 0.06). When FMS and age were included in a multivariable model, there was a significant interaction (p = 0.01) between the two variables. There was a significant increase in the relative risk of LF for age ≤ 45 years (range 11.1–17.4), irrespective of FMS category. Although excellent overall control rates were achieved for patients > 45 years, for younger patients LF rates appeared to remain proportional to the relative closeness of the FMS, despite rigorous dose escalation. Conclusions: Graded tumor-bed dose escalation in response to FMS results in an exceptionally low risk of “early” local recurrence within the first 5 years of follow-up. However, this strategy is unable to completely overcome the longer term adverse influence of young age and positive FMS.

Purpose: Margin assessment is commonly used as a guide to the relative aggressiveness of therapy for breast conserving treatment (BCT), though its value as a predictor of the presence, type, or extent of residual tumor has not been conclusively studied. Controversy continues to exist as to what constitutes a margin that is "positive," "close,", or "negative." We attempt to address these issues through an analysis of re-excision specimens. Methods and Materials: As part of an institutional prospective practice approach for BCT, 265 cases with AJCC Stage III carcinoma with an initial excision margin that was ≤2 mmor indetermine were subjected to re-excision. The probability of residual tumor (+RE) was evaluated with respect to tumor size, histopathologic subtype, relative closeness of the measured margin, the extent of margin positivity graded as focal, minimal, moderate, or extensive, and the extent of specimen processing as reflected in the number of cut sections per specimen volume (S:V ratio). Teh amount of residual tumor was graded as microscopic, small, medium, or large. The histopathologic subtype of tumor in the re-excision specimen was classified as having an invasive component (ICa) or pure DCIS (DCIS). Results: The primary excision margin was positive, >0≤1 mm, 1.2–2 mm, and indeterminate in 60%, 18%, 5%, and 17%, respectively. The predominant histopathologies in the initial excision specimens were invasvie ductal (IDC) (50%) and tumors with an extensive intraductal component (EIC) 43%). The histopathology of the initial excision specimen was highly predictive of the histopathology of tumor found on re-excision, as residual DCIS was found in 60% of +RE specimens with initial histopathology of EIC compared to 26% for IDC ( p = 0.001). Neither the extent of margin positivity nor the extent of tumor in the re-excision were significantly related to the initial histopathologic subtype; however, a +RE was seen in 59% of EIC, 43% of IDC, and 32% of invasive lobular ILC case ( p = 0.01). The extent of margin positivity was siginificantly related to the size of the tumor such that tumor size ≤ 20 mm was associated with a greater probability of focal or minimal margin involvement. Positive margins graded as focal, minimal, moderate/extensive were associated with a +RE in 26%, 58%, and 84%, respectively ( p = 0.001). Further, the extent of positivity was significantly correlated with the extent of residual tumor such that focal/minimal positivity was more commonly associated with micro/small +RE, whereas moderate/extensive positivity was associated with medium/large +RE. When the closest margin of the initial excision specimen was positive, >0≤1 mm, or 1.1–2 mm, a +RE was foudn in 56%, 41%, and 17%, respectively ( p = 0.01) but did not correlate with the amount of residual tumor. The extent of specimen processing as reflected in the S:V ratio did not correlate with the probability of defining a measured margin as positive nor the probability of a +RE. IN a univariate model, the extent of tumor in the re-excision and the histologic type of tumor in the re-excision were significantly association with margin status adn initial histopathology, respectively. The probability of finding a +RE, based on a multivariate model, was associated with the closeness and extent of margin involvement and initial histopathology of an EIC. Conclusion: The relative closeness of tumor to the specimen and the of margin positivity are predictive for residual tumor, though with an error consistent with its limitations as a sampling procedure. The histopathology of tumor in the initial excision is predictive of the type of residual tumor and the extent of margin positivity was correlated with the amount of residual tumor.